Fig. 7: Model of our findings: Lysosomal exocytosis releases pathogenic αSyn species from neurons.
From: Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models
Native αSyn is expressed as a natively unstructured monomer in the cytosol, in equilibrium with an α-helical conformer upon binding the highly curved synaptic vesicle (SV) membrane. Pathogenic processes oligomerize αSyn into β-sheet-rich amyloid-type aggregates of various sizes. We demonstrate here that these larger pathogenic species, generated in the neuronal cytosol, accumulate in neuronal lysosomes over time, possibly due to their high structural and metabolic stability. SNARE-dependent lysosomal exocytosis releases these non-membrane-enveloped aggregates, and this release is upregulated by neuronal activity and cytosolic Ca2+.
